A liver X receptor (LXR), a peroxisome proliferator-activated receptor (PPAR), and a farnesoid X receptor (FXR) are nuclear hormone receptors that belong to a Type II receptor superfamily. These receptors form a heterodimer together with a retinoid X receptor (RXR) and bind to DNA. When a ligand does not bind, the heterodimer binds to DNA and forms a complex together with a corepressor protein; on the other hand, when a ligand binds, a structural change occurs and the corepressor protein is separated and a coactivator protein binds, thereby promoting transcription of a target gene [Hermanson et al., Trends Endocrinol. Metab., 2002, 13: 55-60]. Among nuclear hormone receptors, LXR plays an important role in controlling transcription of a gene that is related to cholesterol metabolism and homeostasis. Examples of such a gene include apolipoprotein E(apoE), ABCA1, ABCG1, ABCG5, ABCG8, cholesterol 7α-hydroxylase, and scavenger receptor Class B Type I [Schwartz et al., Biochem. Biophys. Res. Commun., 2000, 274: 794-802]. In addition, LXR directly affects the SREBP-1c gene and controls lipid metabolism [Yoshikawa et al., Mol. Cell. Biol., 2001, 21: 2991-3000].
LXR has two isomers including LXRα and LXRβ. In most case, LXRα exists in the liver, and LXRβ exists in most organs. LXRα is activated by oxysterols that are natural ligands, high glucose, and T0901017 and GW3965 that are artificial ligands, and controls the expression of genes that relate to lipid synthesis and cholesterol homeostasis. When lipids are produced in the liver, LXRα functions as a lipid sensor and significantly increases the expression and activity of SREBP-1c that is a key transcription factor for controlling expression of lipogenic genes and thus, promotes fatty acid synthesis in liver tissues and increases the amount of triglyceride in blood.
LXRα-induced non-alcoholic liver steatosis may be developed through two different pathways: a SREBP-1c-dependent pathway and a SREBP-1c-independent pathway. SREBP-1c-dependent liver steatosis is developed because lipogenic genes are more expressed through transcription activity of LXRα-mediated SREBP-1c. SREBP-1c-independent liver steatosis is developed because activity of LXRα leads to an increase in expression of a CD36 protein that is a carrier of free fatty acids and thus, more fatty acids are moved to the liver. As described above, the activity of LXRα promotes development of non-alcoholic liver steatosis. However, medicines that inhibit development of liver steatosis by controlling the activity of LXRα have not been developed.
SREBP is a protein that binds to a sterol response element (SRE) that is a transcription control site of a gene that is controlled by sterol, and exists in three isoforms: SREBP-1a, SREBP-1c, and SREBP-2. SREBP-1a and SREBP-1c are transcribed from the same gene, and SREBP-2 is expressed from a different gene. SREBP-1c is a transcription factor for controlling transcription of genes that relates to synthesis of fatty acids, and SREBP-2 is a transcription factor for controlling transcription of genes that relates to synthesis of cholesterol. In an resting condition, SREBP exists in endoplasmic reticulum membrane and the size thereof is 125 kDa. Before being activated by lack of sterol, SREBP binds to a membrane in an inactivated form. Then, when activated, SREBP moves to a Golgi body, and then is broken down into activated proteins having the size of 65 kDa. When activated, SREBP moves into a nucleus and binds to SRE of target genes and increases expression of lipid synthesis genes. Target genes of SREBP-1c are enzymes that promote fatty acid synthesis. Examples of such an enzyme include fatty acid synthase (FAS), acetyl CoA carboxylase (ACC), and stearoyl CoA desaturase (SCD). When the amount of free fatty acids that are moved from the blood into the liver and that are synthesized de novo in the liver is greater than the amount of fatty acids that are secreted into the form of very low density lipoprotein (VLDL) and that are β-oxidized, a lipid metabolism balance in the liver is broken and liver steatosis is developed. Thus, SREBP-1c that induces and controls FAS, ACC, and SCD proteins that promotes fatty acid synthesis is an important factor contributing to alcoholic or non-alcoholic liver steatosis [Kohijma et al., Int. J. Mol. Med., 2008, 21(4): 507-511, Donohue, World J. Gastroenterol. 2007, 13(37): 4974-4978]. Liver steatosis refers to a disease state in which the fat content of the liver is 5% or more of the entire weight of the liver. Liver diseases including liver steatosis are the most common cause of death excluding cancers in adults between the ages of 40 and 50. In industrialized countries, about 30% of the respective populations have symptoms of liver steatosis, and 20% of the cases develop into liver cirrhosis through liver fibrosis. 50% of liver cirrhosis patients die of liver disease within 10 years of being diagnosed with liver cirrhosis. Cases of non-alcoholic liver steatosis are increased due to more westernized high lipid diets and lack of exercise. Currently, the only way of treating liver steatosis is to improve lifestyle factors such as diet.
There are almost no available medicines that are effective for treating liver steatosis, and only exercise and diets are recommended. However, the resultant treatment effects are too low. Thus, there is a need to develop drugs for effectively treating liver steatosis. Meanwhile, betaine, glucuronate, methionine, choline, lipotrophic preparations are used as drug supplement therapy, but medical or pharmaceutical effects of these materials have not been proved. Accordingly, there is a need to develop a drug for effectively treating liver steatosis without side effects.
Meanwhile, SREBP-1 and SREBP-2 are more expressed in kidneys in older people and due to the increased expression of SREBP-1 and SREBP-2, lipid synthesis and accumulation of triglyceride and cholesterol in kidneys are increased, which may cause glomerulosclerosis, proteinuria, and nephropathy [Jiang et al., Kidney Int., 2005, 68(6): 2608-2620].
It is reported that LXRα plays an important role in secretion of renin in the kidney. LXRα and LXRβ all are sufficiently expressed in juxtaglomerular cells that generate renin. According to Morello et al., T0901017 and GW3965, which are agonists of LXRα, increase expression of mRNA of renin in the kidney, and renin activity in blood [Morello et al., J. Clin. Invest., 2005, 115: 1913-1922]. When there is excessive renin in blood, hyperreninemia is developed and thus, hypertension and aldosteronism are developed.
LXR also controls expression of an ABCD2 gene that relates to adrenoleukodystrophy (ALD) and thus, an inhibitor of LXR is effective for treating ALD, wherein ALD is a rare disease caused when a very-long-chain fatty acid (VLCFA) in vivo is not decomposed and enters the brain and destroys nerve cells. [Weinhofer et al., J. Biol. Chem., 2005, 280: 41243-41251].
Dithiolthiones are sulfur-containing compounds, and are found in Brassicaceae vegetables, and some substituents thereof have a liver protection effect. A representative compound of 1,2-dithiolthione is oltipraz(4-methyl-5-(2-pyrazinyl)-1,2-dithiol-3-thione) which was once used to treat schistosomiasis in the early 1980s and to develop a drug for cancer chemoprevention and a drug for treating liver cirrhosis. Oltipraz contributes to an increase in the content of thiol in cells of tissues in vivo, and induces, in addition to the expression of enzymes that relate to maintenance of glutathione (GSH) pool, the expression of enzymes that relate to detoxification of electrophilic materials. Examples of the enzymes whose activities are increased due to oltipraz include NAD(P)H:quinone reductase, microsomal epoxide hydrolase, glutathione S-transferase (GST), and UDP-GT. In particular, GST is an enzyme that prevents hepatotoxicity stemming from toxic materials such as tetrachloride or acetaminophen.
The inventors of the present invention found that oltipraz prevents expression of TGFβ and achieved a patent right to a pharmaceutical composition preventing and treating liver fibrosis and liver cirrhosis (KR No. 10-0404303.) The inventors of the present invention also found that oltipraz increases expression of C/EBPβ-LIP and inhibits expression of C/EBPα and PPARγ genes and achieved a patent right to a drug for preventing and treating obesity (KR No. 10-0576157). The inventors of the present invention also found that 1,2-dithiolthione compounds such as oltipraz enhance kinase activity of RSK1(p90 ribosomal S6 kinase 1) and achieved a patent right to a 1,2-dithiolthione-containing drug for preventing and treating diabetes and complications thereof (KR No. 10-0590818).